Lithium and valproate (VPA) are common mood stabilizers for bipolar disorder and are shown to indirectly regulate intracellular pathways, using molecules like cAMP response element-binding protein (CREB), brain derived neurotrophic factor (BDNF), Bcl-2, and mitogen-activated protein kinases (MAPK), whose activities may produce some of the beneficial effects of the mood stabilizing drugs. Specifically, lithium and valproate upregulate Bcl-2 in vivo and in vitro, preventing neuronal cell death through blocking the mitochondrial program for apoptosis. Accumulating evidence suggests that mitochondrial dysfunction plays a critical role in the progression of a variety of neurodegenerative and psychiatric disorders. Thus, enhancing mitochondrial function could potentially help ameliorate the impairments of neural plasticity and cellular resilience associated with a variety of neuropsychiatric disorders. A series of studies was undertaken to investigate the effects of mood stabilizers on mitochondrial function and mitochondria-mediated neurotoxicity. We found that long-term treatment with lithium and VPA enhanced cell respiration rate. Furthermore, chronic treatment with lithium or VPA enhanced mitochondrial function as determined by mitochondrial membrane potential and mitochondrial oxidation in SH-SY5Y cells. In vivo studies showed that long-term treatment with lithium or VPA protected against methamphetamine-induced toxicity at the mitochondrial level. Furthermore, these agents prevented the methamphetamine-induced reduction of mitochondrial cytochrome c, the mitochondrial anti-apoptotic Bcl-2/Bax ratio, and mitochondrial cytochrome oxidase (COX) activity. DNA microarray analysis demonstrated that the gene expression levels of several proteins related to the apoptotic pathway and mitochondrial functions were altered by methamphetamine, and these changes were attenuated by treatment with lithium or VPA. One of the genes, Bcl-2, is a common target for lithium and VPA. Knockdown of Bcl-2 with specific Bcl-2 siRNA reduced the lithium- and VPA-induced increases in mitochondrial oxidation. These findings illustrate that lithium and VPA enhance mitochondrial function and protect against mitochondria-mediated toxicity. These agents may have potential clinical utility in the treatment of other diseases associated with impaired mitochondrial function, such as neurodegenerative diseases and schizophrenia. In addition, calcium dysfunction in bipolar disorder is considered the most reproducible biological abnormality described in the illness, and recent data support a role for calcium dysregulation in the mitochondrial and endoplasmic reticulum (ER) of individuals with bipolar disorder. Recent human genetic data show that a single nucleotide polymorphism (SNP) in the Bcl-2 geners956572 (variant AA) is a risk allele for bipolar disorder that is also characterized by low Bcl-2 levels and an increased incidence of apoptosis in carriers of the allele. Since Bcl-2 regulates intracellular Ca++ signaling via its effects on the ER and mitochondria, we have examined the functional role of Bcl-2 in intracellular Ca++ regulation in lymphoblasts from bipolar disorder patients presenting three variants (AA, AG or GG) of this Bcl-2 SNP. We found that the Bcl-2-deficient variant AA presents elevated basal cytosolic Ca++ levels, although there were no quantitative differences between SNP variants in luminal ER and mitochondrial calcium concentrations, nor in Ca++ entry. However, increased cytosolic Ca++ levels after inositol 1, 4, 5-trisphosphate (InsP3)-mediated Ca++ mobilization, in parallel with enhanced reduction of the ER calcium pool, were observed specifically in variant AA and mimicked by Bcl-2 inhibitors in variant GG, showing that decreased Bcl-2 levels are associated with enhanced ER Ca++ release via InsP3 receptors. Functional interaction between Bcl-2 and InsP3 receptors appears relevant to the therapeutics of bipolar disorder, since chronic lithium given to human cells carrying the Bcl-2 risk allele AA induced a decrease in the abnormally high basal cytosolic Ca++ levels and in the extent of InsP3-mediated ER Ca++ release. The results demonstrate that Bcl-2 SNP variations in bipolar disorder facilitate deranged calcium signaling through modulation of InsP3-dependent ER Ca++ release.